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Biomedical subjects

J Kurtz

Publications and source records attributed to J Kurtz.

At least 19 recordsLinked to original sources
PubMed2006

Increased risk of acute myeloid leukaemia after treatment for breast cancer.

This study evaluates the risk of acute myeloid leukaemia (AML) in patients treated for breast cancer. We included all 6360 breast cancer patients that were recorded at the Geneva Cancer Registry between 1970 and 1999. Patients were followed for AML occurrence until December 2000. We calculated standardized incidence ratios of AML and identified factors modifying the risk of AML by multivariate Cox analysis. Twelve (0.2%) patients developed AML. In general, patients treated for breast cancer had a 3.5-fold (95% confidence interval (CI): 1.8-6.0) increased risk of developing AML compared with the general population. In particular, patients who were older than 70 years at breast cancer diagnosis and those treated with radiotherapy (with or without chemotherapy) had a significantly increased risk of developing AML. This population-based study confirms that radiotherapy increases the risk of AML. Due to the relatively low number of women treated with chemotherapy without radiotherapy and due to the infrequency of the disease, the question of whether chemotherapy alone increases this risk of AML cannot yet be answered.

Aged↗
PubMed2006

Local differences in immunocompetence reflect resistance of sticklebacks against the eye fluke Diplostomum pseudospathaceum.

We investigated population differences in immunological adaptation of three-spined sticklebacks (Gasterosteus aculeatus) to one of their most abundant macroparasites, the eye fluke Diplostomum pseudospathaceum. We compared infection success in lab-bred fish of 2 populations in northern Germany, from a lake, where eye flukes are prevalent, and a river, where these parasites do not occur. In order to discriminate between protection through innate and acquired immunity, we exposed fish either only once or repeatedly. Lake fish were significantly less susceptible than river sticklebacks already after a single exposure, indicating that in sympatric hosts innate immunity plays the major role in the defence against this helminth infection. In both habitat types, previous exposures only marginally decreased infection rates within 12 weeks. Lake fish showed higher immunocompentence by means of respiratory burst activity and spleen size, regardless of the infection status. Furthermore, they were in a better energy status than river fish, as indicated by a higher hepatosomatic index and haematocrit value. Interestingly, F1 hybrid fish of both populations ranged between the pure habitat types in parasite susceptibility as well as in immunological and condition parameters. Our results suggest that sticklebacks from lakes are better adapted to cope with higher parasite abundance in this habitat.

Adaptation, Physiological↗
PubMed2006

Resistance against heterogeneous sequential infections: experimental studies with a tapeworm and its copepod host.

Parasite heterogeneity is thought to be an important factor influencing the likelihood and the dynamics of infection. Previous studies have demonstrated that simultaneous exposure of hosts to a heterogeneous mixture of parasites might increase infection success. Here this view is extended towards the effect of parasite heterogeneity on subsequent infections. Using a system of the tapeworm Schistocephalus solidus and its copepod intermediate host, heterogeneity of the tapeworm surface carbohydrates is investigated, i.e. structures that are potentially recognized by the invertebrate host's immune system. With lectin labelling, a significant proportion of variation in surface carbohydrates is related to differences in worm sibships (i.e. families). Tapeworm sibships were used for experimental exposure of copepods to either homogeneous combinations of tapeworm larvae, i.e. worms derived from the same sibship or heterogeneous mixtures of larvae, and copepods were subsequently challenged with an unrelated larva to study re-infection. Contrary to expectation, neither an effect of parasite heterogeneity on the current infection, nor on re-infection were found. The effect of parasitic heterogeneity on host immunity is therefore complex, potentially involving increased cross-protection on the one hand, with higher costs of raising a more heterogeneous immune response on the other.

Animals↗
PubMed2006

Genetic variation in MHC class II expression and interactions with MHC sequence polymorphism in three-spined sticklebacks.

Genes of the major histocompatibility complex (MHC) have been studied for several decades because of their pronounced allelic polymorphism. Structural allelic polymorphism is, however, not the only source of variability subjected to natural selection. Genetic variation may also exist in gene expression patterns. Here, we show that in a natural population of three-spined sticklebacks (Gasterosteus aculeatus) the expression of MHC class IIB genes was positively correlated with parasite load, which indicates increased immune activation of the MHC when infections are frequent. To experimentally study MHC expression, we used laboratory-bred sticklebacks that were exposed to three naturally occurring species of parasite. We found strong differences in MHC class IIB expression patterns among fish families, which were consistent over two generations, thus demonstrating a genetic component. The average number of MHC class IIB sequence variants within families was negatively correlated to the MHC expression level suggesting compensatory up-regulation in fish with a low (i.e. suboptimal) MHC sequence variability. The observed differences among families and the negative correlation with individual sequence diversity imply that MHC expression is evolutionary relevant for the onset and control of the immune response in natural populations.

Alleles↗
PubMed2005

Juvenile immune status affects the expression of a sexually selected trait in field crickets.

Parasite-mediated sexual selection theory presumes that variation in sexual traits reliably reflects variation in parasite resistance among available mates. One mechanism that may warrant signal honesty involves costs of immune system activation in the case of a parasitic infection. We investigated this hypothesis in male field crickets Gryllus campestris, whose attractiveness to females depends on characteristics of the sound-producing harp that are essentially fixed following adult eclosion. During the nymphal stage, males subjected to one of two feeding regimes were challenged with bacterial lipopolysaccharides (LPS) to investigate condition-dependent effects on harp development as compared to other adult traits. Nymphal nutritional status positively affected adult body size, condition, and harp size. However, nymphal immune status affected harp size only, with LPS-males having smaller harps than control-injected males. In addition, the harps of LPS-males showed a lesser degree of melanization, indicating an enhanced substrate use by the melanin-producing enzyme cascade of the immune system. Thus, past immune status is specifically mirrored in sexual traits, suggesting a key role for deployment costs of immunity in parasite-mediated sexual selection.

Animal Communication↗
PubMed2004

Modulation of granulocyte responses in three-spined sticklebacks Gasterosteus aculeatus infected with the tapeworm Schistocephalus solidus.

Leukocytes isolated from the head kidney and peripheral blood of 3-spined sticklebacks Gasterosteus aculeatus L. were analysed by means of flow cytometry during infection with the tapeworm Schistocephalus solidus (Müller, 1776). Although parasites increased their body weight continuously throughout the observation period (98 d), proportions of granulocytes increased in blood and head kidney only up to Day 63 post-infection (p.i.). Thereafter, declining proportions of granulocytes were observed in both organs. Thus the relative decrease in granulocyte number was not correlated to a decline in the parasitic load of the fish. To investigate a possible modulatory impact of S. solidus on granulocyte function, head kidney leukocytes were isolated at times before Day 63 p.i. and tested in vitro for their capacity to produce reactive oxygen species (ROS). Head kidney leukocytes from S. solidus-infected fish, analysed immediately after isolation (ex vivo, Day 40 p.i.), exhibited a higher ROS production when stimulated with phorbol myristate acetate (PMA), than leukocytes from naive, sham-treated control fish and fish that had resisted or cleared the infection (exposed but not infected). The latter showed an increased spontaneous ROS production that was not correlated to the numbers of granulocytes present in the head kidney isolates. In infected sticklebacks, spontaneous and PMA-induced ROS production was significantly correlated with numbers of granulocytes present in the head kidney isolates, suggesting that elevated ROS production was due to higher numbers of responding cells rather than an increased capacity of single cells. In vitro, after cultivation for 4 d in the presence of pokeweed mitogen (PWM) or extracts from S. solidus, head kidney leukocytes from control fish showed an increased ROS production and phagocytic activity compared with non-stimulated control cultures. In contrast, head kidney leukocytes from infected fish isolated on Days 48 and 44 p.i., failed to respond to S. solidus antigens in vitro. During S. solidus infection, granulocyte mobilisation resulted in elevated numbers of these cells in head kidneys, but the lack of an in vitro response to S. solidus antigens indicates an in vivo priming of granulocytes by the parasite. These observations may reflect the ability of S. solidus to impair the host's immune response once the parasite is developing in the body cavity of G. aculeatus.

Analysis of Variance↗
PubMed2003

Infantile herpes simplex encephalitis: diagnostic features and differentiation from non-accidental injury.

OBJECTIVES: Neonatal herpes simplex virus (HSV) encephalitis is rare, but associated with considerable morbidity and mortality. After a baby, subsequently proven to have HSE, had initially been diagnosed as non-accidental injury (NAI), we reviewed the clinical features and radiology of infants with HSE recently diagnosed by our laboratory. METHODS: Screening of cerebrospinal fluid (CSF) samples sent to Oxford for HSV polymerase chain reaction (PCR) analysis, from wide range of British hospitals, identified HSV infected infants. After a diagnosis was made, the case notes and neuroradiology (where available) were reviewed and a limited follow-up was undertaken. RESULTS: Thirteen infants had HSV encephalitis (HSE), which in four followed a relapsing course. On subsequent assessment six infants had neurological sequelae, six appeared to be normal, and one was lost to follow-up. Neither a history of primary HSV infection in pregnancy, nor skin lesions in the baby, were helpful diagnostically. Magnetic resonance imaging indicated haemorrhage in the cortex, but no subdural haematomata, a hallmark of NAI, in 5/6 infants. CONCLUSIONS: The early clinical features of HSE and NAI may be indistinguishable. As early diagnosis is important, infants with an unidentified encephalopathic illness should be examined by neuroradiology and their CSF tested for HSV DNA. Together these examinations can confirm and differentiate between those two conditions. Relapsing HSE may mimic recurrent encephalopathy caused by multiple NAIs.

Child Abuse↗
PubMed2002

To avoid or eliminate: cestode infections in copepods.

The outcome of a parasite infection is the result of the interaction between the host and the parasite. In the system we studied, there are 3 critical stages for the outcome of infection of the (intermediate) host, the copepod Macrocyclops albidus, with the cestode Schistocephalus solidus. During the establishment phase of the parasite, the host may firstly avoid ingesting the parasite and, secondly, may prevent the parasite from entering the body cavity and, thirdly, during the growth phase of the parasite, the host's immune system may eliminate the parasite from the body cavity. We were able to study the growth phase separately from the establishment phase. The establishment phase was influenced by characteristics of the host as well as characteristics of the parasites. Small copepods and males performed poorly; they were more often infected and had a lower survival. Parasites from different sib-groups differed in infectivity. During the growth phase some disappearance of parasites was observed. However, this could not be related to any of the studied characteristics of the host, and the sib-groups of parasites did not seem to differ in their likelihood to disappear. Instead, we suggest that disappearance of parasites, once they have entered the body cavity, may be due to intrinsic mortality of the parasites, independent of the host or the sib-group that the parasites belong to. This indicates that the crucial interactions between host and parasite determining the outcome of infection takes place in the short time-period between ingestion and penetration of the gut-wall.

Animals↗
PubMed2002

Altered host behaviour: manipulation or energy depletion in tapeworm-infected copepods?

Parasites are able to influence intermediate hosts in a way that optimizes their growth and transmission to the next host. Macrocyclops albidus (Copepoda) suffer from a reduced escaping ability and an increased level of general activity, when infected with Schistocephalus solidus (Cestoda). This facilitates predation by the subsequent host, the three-spined stickleback. However, instead of adaptive host manipulation by the tapeworm, the altered copepod behaviour might be explained more simply as a constraint of the infection. Energy depletion could lead to decreased muscle performance and increased food searching activity. Furthermore, resource allocation among host tissues might change after infection. We therefore analysed the amount of storage lipids and muscle tissue before and after experimental infection. To determine the amount of muscles, we developed a new polarization-microscopic technique. Irrespective of infection, lipids and muscles were predictors of copepod survival. However, we found no effect of the parasite infection on muscles or lipids, and no indication of a change in resource allocation between these tissues. Our study suggests that behavioural changes in infected copepods are mediated by a mechanism different from energy depletion or a re-allocation of resources between muscles and lipids. We rather propose that the tapeworms directly manipulate copepod behaviour.

Animals↗
PubMed2002

Management of women with ductal carcinoma in situ of the breast: a population-based study.

BACKGROUND: Increasing incidence of ductal carcinoma in situ (DCIS) confronts patients and clinicians with optimal treatment decisions. This multidisciplinary study investigates therapeutic modalities of DCIS in daily practice and provides recommendations on how to increase quality of care. PATIENTS AND METHODS: All women (n = 116) with unilateral DCIS recorded in the Geneva Cancer Registry from 1995 to 1999 were considered. Information concerned patient and tumor characteristics, treatment and outcome. Factors linked to therapy were determined using a case-control approach. Cases were women with treatment of interest and controls other women on the study. RESULTS: Most DCIS cases (62%) were discovered by mammography screening. Ninety (78%) women had breast-conserving surgery (BCS), 18 (16%) mastectomy and seven (6%) bilateral mastectomy. Eight (7%) patients had tumor-positive margins, 18 (16%) lymph node dissection and two (1.7%) chemotherapy. Twenty-five per cent of women with BCS had no radiotherapy, three had radiotherapy after mastectomy. Less than 50% underwent breast reconstruction after mastectomy. Method of discovery, multifocality, tumor localization, size and differentiation were linked to the use of BCS or lymph node dissection. CONCLUSIONS: Because of important disparities in DCIS management, recommendations are made to increase quality of care, in particular to prevent axillary dissection or bilateral mastectomy and to increase the use of radiotherapy after BCS.

Adult↗
PubMed2001

CD4 T cell-mediated alloresistance to fully MHC-mismatched allogeneic bone marrow engraftment is dependent on CD40-CD40 ligand interactions, and lasting T cell tolerance is induced by bone marrow transplantation with initial blockade of this pathway.

Costimulatory blockade can be used to promote allogeneic marrow engraftment and tolerance induction, but on its own is not 100% reliable. We sought to determine whether one or the other of the CD4 or CD8 T cell subsets of the recipient was primarily responsible for resistance to allogeneic marrow engraftment in mice receiving costimulatory blockade, and to use this information to develop a more reliable, minimal conditioning regimen for induction of mixed chimerism and transplantation tolerance. We demonstrate that a single anti-CD40 ligand mAb treatment is sufficient to completely overcome CD4 cell-mediated resistance to allogeneic marrow engraftment and rapidly induce CD4 cell tolerance, but does not reliably overcome CD8 CTL-mediated alloresistance. The data suggest that costimulation, which activates alloreactive CTL, is insufficient to activate alloreactive CD4 cells when the CD40 pathway is blocked. The addition of host CD8 T cell depletion to anti-CD40 ligand treatment reliably allows the induction of mixed chimerism and donor-specific skin graft tolerance in 3 Gy-irradiated mice receiving fully MHC-mismatched bone marrow grafts. Thus, despite the existence of multiple costimulatory pathways and pathways of APC activation, our studies demonstrate an absolute dependence on CD40-mediated events for CD4 cell-mediated rejection of allogeneic marrow. Exposure to donor bone marrow allows rapid tolerization of alloreactive CD4 cells when the CD40 pathway is blocked, leading to permanent marrow engraftment and intrathymic tolerization of T cells that develop subsequently.

Animals↗
PubMed2001

Peripheral deletion after bone marrow transplantation with costimulatory blockade has features of both activation-induced cell death and passive cell death.

Two major pathways of death of previously activated T cells have been described: activation-induced cell death can be triggered by restimulating activated T cells with high concentrations of Ag, is Fas-dependent, is not influenced by proteins of the Bcl family, and is blocked by cyclosporin A; in contrast, passive cell death is induced by the withdrawal of growth factors and activation stimuli, is Fas-independent, and is blocked by Bcl family proteins. We examined the role of these two forms of cell death in the peripheral deletion of donor-reactive host T cells after allogeneic bone marrow transplantation and costimulatory blockade with anti-CD154 plus CTLA4Ig in two murine models. The substantial decline in donor-reactive CD4 cells seen in wild-type recipients 1 wk after bone marrow transplantation with costimulatory blockade was largely inhibited in Fas-deficient recipients and in Bcl-x(L)-transgenic recipients. We observed these effects both in a model involving low-dose total body irradiation and a conventional dose of bone marrow, and in a radiation-free regimen using high-dose bone marrow transplantation. Furthermore, cyclosporin A did not completely block the deletion of donor-reactive CD4(+) T cells in recipients of bone marrow transplantation with costimulatory blockade. Thus, the deletion of donor-reactive T cells occurring early after bone marrow transplantation with costimulatory blockade has features of both activation-induced cell death and passive cell death. Furthermore, these in vivo data demonstrate for the first time the significance of in vitro results indicating that proteins of the Bcl family can prevent Fas-mediated apoptosis under certain circumstances.

Abatacept↗
PubMed2001

Mechanisms involved in the establishment of tolerance through costimulatory blockade and BMT: lack of requirement for CD40L-mediated signaling for tolerance or deletion of donor-reactive CD4+ cells.

We have previously shown that high levels of multiline-age mixed hematopoietic chimerism and systemic T-cell tolerance can be achieved in mice without myeloablation through the use of anti-CD40L and costimulatory blockade alone (plus CTLA4Ig) or with recipient CD8 depletion and allogeneic bone marrow transplantation. Chimeric mice permanently accept donor skin grafts (> 100 days), and rapidly reject third-party grafts. The mechanisms by which costimulatory blockade facilitates the engraftment of allogeneic hematopoietic cells have not been defined. To further understand the in vivo mechanisms by which the administration of anti-CD40L mAb facilitates the engraftment of donor bone marrow and rapidly tolerizes CD4+ T cells, we analyzed the establishment of chimerism and tolerance in CD40L -/- mice. We demonstrate here that anti-CD40L mAb treatment is required only to prevent CD40L/CD40 interactions, and that no signal to the T cell through CD40L is necessary for the induction of CD4+ tolerance. Peripheral deletion of donor-reactive CD4+ T cells occurs rapidly in CD40L -/- mice receiving bone marrow transplantation (BMT), indicating that this deletion in the presence of anti-CD40L is not due to targeting of activated CD4+ cells by the antibody. Complete CD4+ cell tolerance is observed by both skin graft acceptance and in vitro assays before deletion is complete, indicating that additional mechanisms play a role in inducing CD4+ T-cell tolerance as the result of BMT in the presence of CD40/CD40L blockade.

Animals↗